tbuckley/cabot-search huggingface dataset:
Abstract A006: Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study
Authors: Shaneda Warren Andersen, Zoe Walts, Ronni Brent, Lisa Parlato
Journal: Cancer Research (2022)

Abstract Background: Obesity may increase colorectal cancer (CRC) risk, primarily through mechanisms of increased inflammation. BMI is the most commonly used measure of adiposity; however, it may less accurately measure adiposity in Black populations, highlighting the need for biomarkers of inflammation to evaluate risk. Herein, we investigate the associations between BMI, albumin as a biomarker of inflammation, and CRC risk. Methods: Participant data arise from 71,141 participants of the Southern Community Cohort Study, of which 724 were diagnosed with incident CRC; 69% of the cohort are Black, and 56% have household income &amp;lt;$15,000. A subset of 277 cases and 642 controls had serum albumin concentration measured from blood samples taken at enrollment. Controls were selected through incidence density sampling of the cohort and individually matched to cases by age, sex, and race. Cox proportional hazards were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and CRC risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95%CIs for associations between albumin concentrations and CRC risk. WHO categories of BMI and albumin concentration tertiles determined through the control’s distribution were used. Results: Participants with underweight (&amp;lt;18.5) compared to normal (18.5-24.9) BMI had increased CRC risk (HR:1.69, 95%CI:0.95-2.98). Null associations were observed between overweight and obese BMI and CRC risk compared to normal BMI participants. Associations between BMI and CRC risk did not vary by sex or race (p-interactions&amp;gt;0.05). Albumin concentration was lower in Black participants and inversely associated with CRC risk (per-standard-deviation increase: OR:0.86, 95%CI:0.74,0.99). Associations were most apparent in participants who self-identified as Black race (OR 0.81, 95%CI:0.68,0.97), or female (OR:0.80, 95%CI:0.65,0.98). There was no evidence that albumin mediated the association between BMI and CRC risk, however BMI modified the association between albumin and CRC (BMI &amp;lt;30: OR: 0.90 95%CI:0.73,1.11; BMI ≥30: OR:0.75, 95%CI:0.60,0.95; p-interaction=0.07). Conclusions: Our results support the role of an inflammatory mechanism to increase CRC risk. The null associations between overweight and obese BMI with CRC risk displays the limited predictive utility of BMI in Black populations. Lower albumin concentrations and increased inflammation in Black populations, particularly in the presence of increased adiposity, may represent a contributing factor to racial disparity in CRC incidence. Citation Format: Shaneda Warren Andersen, Zoe Walts, Ronni Brent, Lisa Parlato. Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A006.
Abstract PR007: Intestinal intraepithelial T cells limit colorectal cancer progression
Authors: Sonia Ghilas, Dinesh Raghu, Kelly Tran, Yang Liao, Bhupinder Pal, Shoukat Sterle, Christine Dijkstra, Marina Yakou, Pavitha Parathan, John Mariadason, Matthias Ernst, Andreas Behren, Grant Drummond, Wei Shi, Lisa A. Mielke
Journal: Cancer Research (2022)

Abstract Homeostasis in the gut is achieved by impeccable functioning of tissue resident immune cells that reside and closely interact with the epithelium. The tissue resident immune cells of the intestinal epithelium are predominantly lymphocytes, known as intraepithelial lymphocytes (IELs) and mainly consist of TCRαβ T cells and TCRgd T cells. These IELs are well known to sense microbes, nutrients, and cellular stress but their role in intestinal cancer progression has been controversial. On one hand, gd Τ cells are the primary source of IL-17, an important proinflammatory cytokine that aid in colorectal cancer (CRC) progression. On the other hand, mice lacking gd Τ cells have been showed to have an increased risk of developing carcinogen-induced CRC. Here we used two different mouse model of colon cancer to investigate the role of gd T IELs in colon tumor growth. We showed that in both orthotopic implantation of cancer cells in the colon, and inflammation-driven colon cancer models, gd T cells are essentials to limit tumor growth. Indeed, mice lacking gd T cells had increased tumor incidence with high-grade adenomas compared to control mice. We also performed gene expression analysis of the adenomas in control mice and in mice lacking gd T cells. They revealed distinct transcription profiles with CRC-associated gene expression profile, including inflammatory genes and epithelial to mesenchymal transition genes, particularly enriched in adenomas from gd T cell deficient mice. Moreover, using human tissue microarrays, we investigated whether the presence of gd T cells in tumors of patients with advanced CRC could be used to predict disease outcomes. We revealed that patient disease-free survival was improved if gd T cells could be detected within tumors. Therefore, we showed that gd T cells are primordial in limiting colorectal cancer progression in both mice and humans. Citation Format: Sonia Ghilas, Dinesh Raghu, Kelly Tran, Yang Liao, Bhupinder Pal, Shoukat Sterle, Christine Dijkstra, Marina Yakou, Pavitha Parathan, John Mariadason, Matthias Ernst, Andreas Behren, Grant Drummond, Wei Shi, Lisa A. Mielke. Intestinal intraepithelial T cells limit colorectal cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR007.
Viscoelastic Notch Signaling Hydrogel Induces Liver Bile Duct Organoid Growth and Morphogenesis (Adv. Healthcare Mater. 23/2022)
Authors: Muhammad Rizwan, Christopher Ling, Chengyu Guo, Tracy Liu, Jia‐Xin Jiang, Christine E. Bear, Shinichiro Ogawa, Molly S. Shoichet
Journal: Advanced Healthcare Materials (2022)

Mechanotransduction In article 2200880 by Molly S. Shoichet and co-workers, an engineered hyaluronan hydrogel elucidates cell–matrix interactions and bile duct morphogenesis. The hydrogel viscoelasticity is systematically varied to promote primary cholangiocyte organoid growth from encapsulated single cells, which is mediated by Yes-associated protein signaling. The immobilized Jagged1 in the hydrogel activates Notch signaling in 3D cultured cholangiocytes, which leads to unprecedented bile duct-like morphogenesis.
High Throughput Omnidirectional Printing of Tubular Microstructures from Elastomeric Polymers (Adv. Healthcare Mater. 23/2022)
Authors: Chuan Liu, Scott B. Campbell, Jianzhao Li, Dawn Bannerman, Simon Pascual‐Gil, Jennifer Kieda, Qinghua Wu, Peter R. Herman, Milica Radisic
Journal: Advanced Healthcare Materials (2022)

Biomimicking In article 2201346 by Milica Radisic and co-workers, scaffolds fabricated by coaxial printing of bioelastomers can mimic both the structures and mechanical properties of native tissues, which are ideal for organ-on-a-chip and tissue engineering applications. This image shows an artistic tubular structure made of a biodegradable elastomer called PICO.
Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration (Adv. Healthcare Mater. 23/2022)
Authors: Dax Calder, Ali Fathi, Farshad Oveissi, Simin Maleknia, Terence Abrams, Yiwei Wang, Joanneke Maitz, Kevin Hung‐Yueh Tsai, Peter Maitz, Wojtek Chrzanowski, Ivan Canoy, Vivek Ashoka Menon, Kenneth Lee, Benjamin J. Ahern, Natasha E. Lean, Dina M. Silva, Paul M. Young, Daniela Traini, Hui Xin Ong, Rasoul Seyed Mahmoud, Hossein Montazerian, Ali Khademhosseini, Fariba Dehghani
Journal: Advanced Healthcare Materials (2022)

Injectable Hydrogels The coil structure represents the synthetic chemical composition of the featured biomaterial. The fluid network is temperature responsive and transitions into an adhesive hydrogel matrix upon administration. The resulting scaffold moulds within any defect and provides a regenerative network for cell in growth and subsequent tissue regeneration. The work represented here can be found in article 2201714 by Ali Fathi, Fariba Dehghani, and co-workers.
Abstract IA018: Reading and writing extrachromosomal DNA
Authors: Howard Y. Chang
Journal: Cancer Research (2022)

Abstract Cancer patients face an extraordinary challenge when oncogenes unleash themselves from chromosomes. Extrachromosomal DNA (ecDNA) are large, megabase-sized circular episomes containing oncogenes and regulatory DNA elements. EcDNAs have a remarkable transcriptional advantage and rapidly change copy number–a moving target driving accelerated evolution in cancer. We present a method for targeted purification of megabase-sized ecDNA by combining in-vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA (CRISPR-CATCH). Targeted purification of ecDNA versus chromosomal DNA enabled phasing of genetic variants and provided definitive proof of oncogenic mutations exclusively on ecDNAs, discovery of ecDNA-specific demethylation with single molecule resolution, and accurate reconstruction of megabase- sized ecDNA structures with base-pair resolution. We model and test the impact of non-chromosomal oncogene inheritance—random identity by descent—on ecDNA on variation and selection. Integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA generation, and live-cell imaging, we identify a set of basic “rules” for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatment. These new tool kits for reading and writing ecDNAs promise to unravel the genetic and epigenetic landscapes of ecDNA biogenesis, dynamics, and function. Citation Format: Howard Y. Chang. Reading and writing extrachromosomal DNA. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA018.
Abstract IA022: Aberrant transcriptional condensates in cancer: Mechanisms and implications
Authors: Liling Wan
Journal: Cancer Research (2022)

Abstract While growing evidence suggests the prevalence of nanoscale protein condensates on chromatin, their mechanisms of formation and functional significance in normal and disease states remain largely unclear. I will present our ongoing work linking aberrant condensates and cancer. In Wilms tumor and leukemia, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation activity. We discover that these mutations, clustered in ENL’s structured acetyl-binding YEATS domain, trigger aberrant condensates at endogenous genomic targets through a network of multivalent homotypic and heterotypic interactions. Crystal structures of four different ENL mutant YEATS domains reveal structural changes critical for condensate formation. In addition, two oppositely charged disordered regions in ENL mutants play distinct yet complementary roles in regulating the initiation and growth of condensates. ENL mutant condensates enrich for an aberrantly high amount of transcription elongation factors which, in turn, also contribute to condensate formation. Importantly, perturbing these condensates in situ via extensive mutagenesis establish their causal role in oncogenic gene activation. Interestingly, expression of ENL mutants beyond endogenous levels results in larger droplet-like condensates that suppress oncogenic gene activation, indicating a dosage-sensitive function of oncogenic proteins prone to condensation. Together, by elucidating how cancer-associated transcriptional condensates occur and function, our work reveals a poorly recognized role of structured domains in the formation of biomolecular condensates and lends crucial experimental support to establish condensate dysregulation as an under-appreciated oncogenic mechanism. These insights would open new areas of investigation and nominate novel therapeutic approaches. Citation Format: Liling Wan. Aberrant transcriptional condensates in cancer: Mechanisms and implications. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA022.
Abstract PR008: An epigenetic memory of inflammation controls context-dependent lineage plasticity and KRAS-driven tumorigenesis in the pancreas
Authors: David J. Falvo, Adrien Grimont, Paul Zumbo, Julie L. Yang, Alexa Osterhoudt, Grace Pan, Andre F. Rendeiro, John Erby Wilkinson, Friederike Dundar, Olivier Elemento, Rhonda K. Yantiss, Doron Betel, Richard Koche, Rohit Chandwani
Journal: Cancer Research (2022)

Abstract Tissue homeostasis depends on responses to environmental insults to restore cellular phenotype, microenvironment composition, and tissue architecture. Inflammation is essential to the disruption of homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Herein we employ lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveil the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that both persistent chromatin and transcriptional changes constituting memory are recalled with oncogenic stress. Together, our findings define a capacity for an environmental insult to control future cell-fate decisions in a context-dependent manner. The ability of epigenetic memory to potentiate tumor initiation both broadens the relationship between inflammation and cancer and raises the possibility that inducing epigenetic ‘amnesia’ of an inflammatory insult could be leveraged as a novel cancer prevention strategy. Citation Format: David J. Falvo, Adrien Grimont, Paul Zumbo, Julie L. Yang, Alexa Osterhoudt, Grace Pan, Andre F. Rendeiro, John Erby Wilkinson, Friederike Dundar, Olivier Elemento, Rhonda K. Yantiss, Doron Betel, Richard Koche, Rohit Chandwani. An epigenetic memory of inflammation controls context-dependent lineage plasticity and KRAS-driven tumorigenesis in the pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR008.
Abstract A015: Cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Authors: Xiao Chen, Yinglu Li, Chao Lu
Journal: Cancer Research (2022)

Abstract Interplays between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes encoding nuclear proteins using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 84 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex functions and biochemical interactions, and predict new chromatin crosstalk, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality. Citation Format: Xiao Chen, Yinglu Li, Chao Lu. Cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A015.
Abstract A028: Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells
Authors: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend
Journal: Cancer Research (2022)

Abstract While localized prostate cancer (PCa) has a high treatment success rate, over 30,000 individuals in the United States and 350,000 men globally die each year from therapy resistant, metastatic PCa. A thorough understanding of the factors contributing to PCa recurrence following development of therapy resistance is acutely needed in order to develop efficacious treatments and disease-management strategies. Our group and others have identified a unique minority population of physically enlarged cancer cells with polyaneuploid genomes, termed polyaneuploid cancer cells (PACCs), in the tumors of patients with metastatic prostate cancer and in other tumor types. PACCs are the result of a polyaneuploid transition that occurs when aneuploid cancer cells experience environmental or therapeutic stress. These aneuploid cancer cells then pause their cell cycle after whole genome doubling to survive the environmental insult. Cancer cells in the PACC state appear to be quiescent and have an increased capacity for invasion/motility, an ability to endure in stressful or novel environments, and a propensity to undergo depolyploidization to re-establish the cancer cell population. We hypothesize that PACCs are critical players in prostate cancer therapy resistance and recurrence. We seek to better understand the life cycle of the PACC state in PCa in order to inform the design of new therapeutic strategies that prevent disease recurrence. Our data suggests that PCa cells in the PACC state tend to have a large polyploid single nucleus more frequently than multiple smaller, single nuclei, though both are observed at all timepoints in PACC recovery. Nuclear morphology and size certainly will impact the way that a cell organizes and utilizes its genome. Additionally, genome organization and stability have been demonstrated to be important factors/drivers of cancer development, progression, and recurrence. Importantly, epigenetic changes such as histone modifications can drastically affect chromatin condensation, which subsequently can alter the gene accessibility and transcription profile of a cell. We hypothesize that cancer cells in the PACC state have different histone modifications and different regions of accessible chromatin compared to parental cancer cells, and that these differences will also impact the gene expression of PACCs. Citation Format: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend. Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A028.
Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons
Authors: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons. Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.